1. To screen a series of DNA-binding drugs showing AT-specificity, testing their ability to inhibit the polymerase activity of HIV reverse transcriptase (RT), more particularly the inhibition of (+) strand synthesis from its polypurine primer. 2. To study crystallography the specific interactions of these drugs with oligomers of DNA-DNA and DNA-RNA of sequence related to that of polypurine (+) strand primer/template complex, looking among other things for evidence of a particular sequence-dependent conformation of the primer/template complex, or of a structural transition produced by binding of the drug. 3. To examine crystallography the complex of (+) strand primer/template, drug, and reverse transcriptase, in order to learn how binding of drug causes inhibition of the polymerase function of the enzyme. Specific Aims 1. We will study the relative binding abilities of a series of generally AT-specific minor groove-binding drugs to various primer/template analogues, including oligo(dT) poly(rA). We also will examine the relative efficiencies of these drugs in inhibiting the polymerase activity of RT. Drug testing is being done in collaboration with Prof. J. William Lown of the University of Alberta, Edmonton. 2. We hope to crystallize complexes of the most promising drugs with an RNA-DNA duplex having a sequence related to some component of the (+) strand primer, r(U-U-U-U-U-A-A-A-A-G-A-A-A-A-G-G-G-G-G-G-A), testing the hypothesis that this region remains untouched by RNase H digestion, and serves as a favorable binding site for groove-binding drugs, because it possesses a particular structure different from the A helix that would ordinarily be expected of an RNA-DNA hybrid duplex. 3. As a longer-range goal, we eventually hope to crystallize a ternary complex of RT, primer/template duplex, and drug molecule, in order to find out how inhibition of polymerase activity comes about. Reverse transcriptase for all of our studies has been provided by Dr. Steve Hughes at the National Cancer Institute, Frederick, MD. This analysis of the ternary structure complex will be assisted by knowledge of the structure of the RT enzyme alone, from the laboratories of Prof. E.A. Arnold of Rutgers and of Prof. Tom Steitz at Yale.